It is known that about 15 million Americans are chronically exposed to environmental arsenic whereas the global picture of arsenic exposure is much grimmer as more than 100 million humans throughout the world consume arsenic contaminated drinking water. Inorganic arsenic is a known human carcinogen and therefore is a well-defined threat to human health. Epidemiological data indicate that chronic human exposure to arsenical compounds is associated with an increased incidence of cancers of the lung, skin (both basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs)), bladder, liver, prostate as well as in other organs. However, the mechanism(s) underlying the carcinogenicity of arsenicals remains elusive particularly due to unavailability of suitable murine model. Originally described in patients with the nevoid basal cell carcinoma syndrome (NBCCS), mutations in sonic hedgehog (shh) signaling genes including patched (ptch), and smoothened (smo) are also known to underlie sporadic BCCs. It is reported that BCCs in arsenic-exposed individuals may also carry ptch mutations. Shh activation including that due to mutations in ptch/smo drives overexpression of transcription factors, gli, which ultimately lead to proliferation of neoplastic lesions. The Shh signaling pathway is one of the most fundamental signal transduction pathways during embryonic development. In this proposal, we will investigate whether aberrant activation of shh pathway is involved in the molecular pathogenesis of arsenic-induced skin cancers (BCCs and SCCs) and possibly in other arsenic- induced cancers. We will also test whether blocking shh activation may reduce the risk of arsenic-induced cancer. In addition, we will investigate the role of arsenic-induced reactive oxygen species (ROS) and associated cell signaling related to stress and cell survival pathways as well as the possible additive or synergistic effects of ROS on shh in augmenting cell proliferation during arsenic-induced skin carcinogenesis. We will utilize our recently developed murine model, ptc1/SKH-1 hairless mice, which are highly susceptible to the induction of both BCCs and SCCs. These studies will provide insights into the mechanisms involved in arsenic-induced human skin carcinogenesis utilizing a highly relevant murine model and could lead to important advances in mechanism-based chemoprevention of these skin neoplasms in arsenic-exposed humans. PUBLIC HEALTH RELEVANCE: Arsenic is a known human carcinogen and a well defined threat to human health. About 15 million Americans and more than 100 million humans throughout the world are chronically exposed to this carcinogen and this exposure is responsible for the enhanced risk of lung, skin, bladder, liver, prostate and other cancers. However, the mechanism of arsenic-induced carcinogenesis is largely elusive, particularly due to lack of suitable animal models. This grant application focuses on the development of a murine model that can recapitulate cutaneous lesions induced by arsenic in humans. These studies are likely to provide the molecular targets which may be involved in arsenic mediated skin carcinogenesis and may eventually lead to the development of cancer chemopreventive and therapeutic protocols for arsenic-induced neoplasm.